Nitriles Lewis acid catalyzed reactions

Stoichiometric amount of methyl aluminum p-binaphthoxide as the Lewis acid. This reaction has recently been extended to a catalytic enantioselective version using an enantiopure methylaluminum p-binaphthoxide (Scheme 11.59) (210,211). Although the actual reacting species were not assigned, 5-alkoxyoxazoles behave as nitrile ylide 1,3-dipole equivalents in Lewis acid catalyzed reactions with aldehydes. 

A common and effective direct approach to unsubstituted or multiply substituted oxazolines is the Lewis acid catalyzed reaction of nitriles with amino alcohols in an alcoholic or aromatic solvent (chlorobenzene) at reflux. The most common Lewis acids employed include ZnCl2, ZnBr2, NiBr2, CuCl2, and kaolinitic clay. Microwave irradiation has also been reported to facilitate the transformation. Alternatively, the condensation can be carried out in the presence of catalytic amounts of potassium carbonate. The method works well for both aliphatic and aromatic nitriles, with retention of stereochemistry. Some representative examples from the recent literature are listed in Table 8.16 (Scheme 3 40),2 35.2oi-2i3... 

The Lewis acid-catalyzed reaction of epoxides with cyanotrimethylsilane (Me3SiCN) forms /3-siloxy nitriles.252 Highly enantioselective desymmetrization of / >-epoxides with Me3SiCN can be achieved by chiral Ti and Yb catalysts (Equation (67)).255 256... 

The Lewis acid-catalyzed reaction of epoxides with TMSCN leads to the formation of -siloxy-nitriles or -isonitriles [604]. The reaction pathway depends mainly on the Lewis acid used. The Yb(CN)3-catalyzed reaction of epoxides proceeds stereospecifically to give y3-siloxynitriles in good yields (Scheme 10.238) [624a]. 

On the other hand, Lewis acid sites are also detected, e.g., by adsorption of pyridine, nitriles and CO [60], which can be remarkably strong. CO adsorption being, as usual, very informative, is reported in detail below. The strength of Lewis sites makes H-[A1]-MTS systems interesting catalysts for Lewis-acid catalyzed reactions, such as, e.g., the dehydrochlorination and the steam reforming of halided hydrocarbons [62]. 

In a totally different Lewis acid catalyzed reaction, benzo[ C]nitrile reacted with an anilinoborane to give specifically the ortho-amino substituted [carbonyl- C]benzophe-none in good yield. ... 

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

As a mle, the reaction at lower temperature catalyzed by SnCU (method B) showed the higher stereoselectivity. Besides small amounts of the starting imine 89, the crude products 90 only contained a few percent of the corresponding a-anomeric amino nitriles presumably produced by a Lewis acid-catalyzed anomerization of the p-anomeric amino nitriles 90. 

Synthesis of Chiral Auxiliaries. Their availability and crystalline nature has made camphor derivatives the precursors of choice for the design and synthesis of chiral auxiliaries. 10-Camphorsulfonyl chloride is the starting material for the synthesis of chiral auxiliaries (9)-(12) (eq 2). Sulfonamides (9) and (10) have been used as chiral auxiliaries in a number of reactions, e.g. the Lewis acid-catalyzed Diels-Alder reaction, the [3 + 2] cycloaddition of a nitrile oxide to an acrylate, and the stereoselective conjugate addition reaction of organocopper reagents to ci ,)3-unsaturated esters. ... 

Trimethylsilyl [ C]cyanide is conveniently accessible from trimethylsilyl chloride, Na CN and Nal in the presence of lutidine or pyridine ". In carbon-14 synthesis it is normally generated in situ and used immediately in subsequent Lewis acid catalyzed chemical transformations. It is useful for some reactions in which alkah metal [ " C]cyanides normally fail, such as cyanide addition to acetals and aromatic and heteroaromatic aldehydes and ketones. Examples include the Znl2-catalyzed addition of TMS " CN to 2-furaldehyde followed by hydride reduction of the resultant silylated cyanohydrin to the aminoalcohol 96 " and the SnCLj-catalyzed formation of D-[l- " C]allonitrile 98, obtained from reaction of TMS " CN to the 0-acetylated hemiacetal 97 (Figure 7.26). Subsequent addition of H2Se to the nitrile group, cyclocondensation of the intermediate selenoamide in situ with ethyl bromopymvate and deprotection yielded 99, precursor to [2- " C]CI-935, a compound with... 

Nitronates derived from primary nitroalkanes can be regarded as a synthetic equivalent of nitrile oxides since the elimination of an alcohol molecule from nitronates adds one higher oxidation level leading to nitrile oxides. This direct / -elimination of nitronates is known to be facilitated in the presence of a Lewis acid or a base catalyst [66, 72, 73]. On the other hand, cycloaddition reactions of nitronates to alkene dipolarophiles produce N-alkoxy-substituted isoxazolidines as cycloadducts. Under acid-catalyzed conditions, these isoxazolidines can be transformed into 2-isoxazolines through a ready / -elimination, and 2-isoxazolines correspond to the cycloadducts of nitrile oxide cycloadditions to alkenes [74]. 

An analogous reaction is the Houben-Hoesch reaction,(sometimes called the Hoesch reaction) using nitriles 7 to give aryl ketones 8. This reaction also is catalyzed by Lewis acids often zinc chloride or aluminum chloride is used. The Houben-Hoesch reaction is limited to phenols—e.g. resorcinol 6—phenolic ethers and certain electron-rich aromatic heterocycles ... 

In addition, the mechanism of the zinc-catalyzed [3+2] dipolar cycloaddition of azides and nitriles to form tetrazoles was examined <2003JA9983>. The energy barrier of the reaction is lowered by 5-6kcalmol 1 which corresponds to an acceleration of 3 1 orders of magnitude. The source of the catalytic activity seems to be the coordination of the Lewis acidic zinc halide to the nitrile, which is supported by model calculations. Also AICI3 was examined as another Lewis acid which catalyzes the reaction to a greater extent than ZnBr2-... 

Further development of this idea led to the proposal (56) that reactive B=C groups, for instance carbonyl systems, would be able to activate alcohol acceptors AH by generating a related A—B—C—H intermediate (Scheme 8, path I). It seemed that chloral might act as a catalyst along these lines. However, it turned out that the rate of decay in the transition state is too low in all systems tested thus far. Therefore, the carbonyl compound is more or less a substitute for a Lewis acid catalyst, as indicated in Scheme 8, path II. The high reactivity and diastereoselectivity in chloral-catalyzed reactions is attributable to the nitriles used as solvents in these reactions [see Section III.3.b and Ref. (62)]. 

Control of reaction selectivities with external reagents has been quite difficult. Unsolved problems remaining in the held of nitrile oxide cycloadditions are (a) Nitrile oxide cycloadditions to 1,2-disubstituted alkenes are sluggish, the dipoles undergoing facile dimerization to furoxans in most cases (b) the reactions of nitrile oxides with 1,2-disubstituted alkenes nonregioselective (c) stereo- and regiocontrol of this reaction by use of external reagents are not yet well developed and (d) there are few examples of catalysis by Lewis acids known, as is true for catalyzed enantioselective reactions. 

Yamamoto and co-workers (135,135-137) recently reported a new method for stereocontrol in nitrile oxide cycloadditions. Metal ion-catalyzed diastereoselective asymmetric reactions using chiral electron-deficient dipolarophiles have remained unreported except for reactions using a-methylene-p-hydroxy esters, which were described in Section 11.2.2.6. Although synthetically very useful and, hence, attractive as an entry to the asymmetric synthesis of 2-isoxazohnes, the application of Lewis acid catalysis to nitrile oxide cycloadditions with 4-chiral 3-(2-aIkenoyl)-2-oxazolidinones has been unsuccessful, even when > 1 equiv of Lewis acids are employed. However, as shown in the Scheme 11.37, diastereoselectivities in favor of the ffc-cycloadducts are improved (diastereomer ratio = 96 4) when the reactions are performed in dichloromethane in the presence of 1 equiv of MgBr2 at higher than normal concentrations (0.25 vs 0.083 M) (140). The Lewis acid... 

TL627>. Other metal-catalyzed reactions include the CdC -mediated cyclization of enamines in the presence of a cyano substituent (Scheme 98) <1995JOC5243>. Zinc and copper (i) salts can be used in place of the cadmium however, organocadmium promoters allow room temperature cyclization. A two-step process involving tungsten alkynols, aldehydes, and nitriles in the presence of a Lewis acid yields pyridines (Scheme 99) <1998JA4520>. 

In that way, two independent paths for the reaction of carbonyl compounds with nitriles under alternative electrophilic activation of either components have been found experimentally. Both are catalyzed by protic and Lewis acids. In this connection, the problem arises which of the two reaction mechanisms takes place. In order to solve this problem theoretical calculations on the reaction pathways have been performed. 

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